Several infections have been implicated in atherogenesis. We have shown that the number of infections correlates with the risk of developing coronary artery disease (CAD). We hypothesized that infections predispose to CAD by inducing endothelial dysfunction. Methods: Serum was collected for IgG antibodies to Cytomegalovirus, Hepatitis A virus, Herpes simplex virus type 1, Chlamydia pneumoniae and Helicobacter pylori from 231 patients (85 with normal coronaries [NCA] and 126 with CAD). Endothelium-dependent and -independent vasodilation was tested with intracoronary acetylcholine (ACH, 30mcg/min) and sodium nitroprusside (SNP, 40mcg/min), respectively, and flow reserve with adenosine (ADO, 2.2 mg/min). Blood flow velocity was measured using a Doppler wire, and change in coronary blood flow (DFlow) and vascular resistance (DCVR) calculated. Results: There was progressive deterioration in endothelial function (ACH-response), but not SNP or ADO responses with increasing exposure to pathogens, Table; patients with 4 or 5 past infections had depressed ACH responses vs the 0-1 infection group. The number of past infections predicted DFlow (p<0.003) and DCVR (p<0.006) in response to ACH, independent of age, gender, CAD, body mass index, serum cholesterol, hypertension, diabetes, and smoking history. ACH response was also depressed in the NCA subgroup; (DFlow with ACH 185% vs. 79%, p=0.004, in 0-1 vs. 4,5 infection groups). Conclusion: Prior infection with these pathogens is a risk factor for coronary endothelial dysfunction, and supports a pathophysiological role of infection in CAD. D Flow (%)No. of Infections ACH SNP Adenosine 0-1 137 123 2782-3 116 125 3344-5 78* 121 280(mean), * p<0.01 for comparison between 0-1 vs 4-5